This application is a 371 of PCT/EP99/02748, filed Apr. 23, 1999.
The present invention relates to formulations comprising particulate products which may be prepared by methods and apparatus using supercritical fluids. More particularly, the invention relates to formulations comprising certain crystalline forms of 4-hydroxy-xcex11-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol (salmeterol) 1-hydroxy-2-naphthalenecarboxylate (xinafoate).
Salmeterol is a selective and potent xcex22 adrenoreceptor stimulant bronchodilator which has been very successfully used by inhalation for the immediate relief of spasm in asthma. Salmeterol is described in British Patent Specification No. 2140800. The xinafoate salt of salmeterol is a particularly preferred pharmaceutically acceptable salt for use in inhalation therapy.
The use of aerosols to administer medicaments by inhalation has been known for several decades. Such aerosols generally comprise the medicament, one or more chlorofluorocarbon propellants and either a surfactant or a solvent, such as ethanol. The most commonly used aerosol propellants for medicaments have been propellant 11 (CCl3F) and/or propellant 114 (CF2ClCF2Cl) with propellant 12 (CCl2F2). However these propellants are now believed to provoke the degradation of stratospheric ozone and there is thus a need to provide aerosol formulations for medicaments which employ so called xe2x80x9cozone-friendlyxe2x80x9d propellants.
A class of propellants which are believed to have minimal ozone-depleting effects in comparison to conventional chlorofluorocarbons comprise fluorocarbons hydrogen-containing fluorocarbons and hydrogen-containing chlorofluorocarbons, and a number of medicinal aerosol formulations using such propellant systems are disclosed in, for example, EP 0372777, WO91/04011, WO91/11173. WO91/11495, WO91/14422, WO92/00107, WO93/08447, WO93/08446. WO93/11743, WO93/11744 and WO93/11745. These applications are all concerned with the preparation of pressurised aerosols for the administration of medicaments and seek to overcome the problems associated with the use of the new class of propellants, in particular the problems of stability associated with the pharmaceutical formulations prepared.
Conventionally crystallised salmeterol xinafoate, even after micronisation (fluid milling), exists in a form with poor flow characteristics, for example it is cohesive and statically charged, which results in difficulties in handling the drug substance in pharmaceutical formulation processes and can, when the drug is mixed with fluorocarbon, hydrogen-containing fluorocarbon or hydrogen-containing chlorofluorocarbon propellants, lead to dispersion stability problems such as drug agglomeration or deposition onto components of the aerosol can, valve or actuator.
We have now surprisingly found that it is in fact possible to obtain satisfactory dispersions of salmeterol xinafoate in fluorocarbon, hydrogen-containing fluorocarbon or hydrogen-containing chlorofluorocarbon propellants such as 1,1,1,2-tetrafluoroethane (propellant 134a, or HFA 134a) by use of salmeterol xinafoate with a controlled particle size, shape and morphology.
International patent application PCT/GB94/01425 published under No. WO95/01324 (the disclosure of which is hereby incorporated herein by reference) describes a method and apparatus suitable for the formation of particulate salmeterol xinafoate in a controlled manner utilising a supercritical fluid particle formation system. The apparatus, further details of which are set out below, comprises a particle formation vessel with means for controlling the temperature of said vessel and means for controlling the pressure of said vessel, together with a means for the co-introduction into said vessel of a supercritical fluid and a vehicle containing at least one substance (such as salmeterol xinafoate) in solution or suspension, such that dispersion and extraction of the vehicle occur substantially simultaneously by the action of the supercritical fluid. The simultaneous co-introduction of the vehicle containing at least one substance in solution or suspension and the supercritical fluid, according to the method described in WO95/01324, allows a high degree of control of parameters such as temperature, pressure and flow rate, of both vehicle fluid and supercritical fluid, at the exact point when they come into contact with one another. This gives a high degree of control over the conditions under which particles of the drug substance suspended or dissolved in the vehicle form and thus of the physical properties of the particles formed.
Accordingly, the present invention provides an aerosol pharmaceutical formulation comprising salmeterol xinafoate with a controlled particle size, shape and morphology, and a fluorocarbon, hydrogen-containing fluorocarbon or hydrogen-containing chlorofluorocarbon propellant. Use of such particulate crystalline forms can give particular benefits in relation to reduction of agglomeration and of deposition of drug onto aerosol can walls, actuator and valve components and may permit the formation of stable dispersions without the use of additional components such as surfactants or co-solvents, or with relatively low levels of such components. Adsorption of drug into rubber components of the valve and/or actuator may also be reduced. Minimising and preferably avoiding the use of formulation excipients e.g. surfactants, cosolvents etc. in the aerosol formulations according to the invention may be advantageous since the formulations may be substantially taste and odour free, less irritant and less toxic than conventional formulations. Preferably the propellant is 1,1,1,2-tetrafluoroethane (propellant 134a), in which formulations the weight ratio of drug to propellant is preferably between 0.025:75 and 0.1:75, for example 0.05:75.
Further advantages for particles formed by the supercritical fluid particle formation method and apparatus include control over the quality of the crystalline and polymorphic phases, since the particles will experience the same stable conditions of temperature and pressure when formed, as well as the potential of enhanced purity. This latter feature can be attributed to the high selectivity of supercritical fluids under different working conditions, enabling the extraction of one or more of the impurities from the vehicle containing the substance of interest.
Moreover, the co-introduction of the vehicle and supercritical fluid, leading to simultaneous dispersion and particle formation, allows particle formation to be carried out, if desired, at temperatures at or above the boiling point of the vehicle, something not possible using previous supercritical fluid particle formation techniques. This enables operation in temperature and pressure domains which were previously inaccessible, which in turn can allow the formation of products, or particular forms of products, that previously could not have been achieved.
Control of parameters such as size and shape in the particulate product will be dependent upon the operating conditions used when carrying out the supercritical fluid method. Variables include the flow rates of the supercritical fluid and/or the vehicle containing substance(s), the concentration of the substance(s) in the vehicle, and the temperature and pressure inside the particle formation vessel. Thus the provision of formulations comprising salmeterol xinafoate as prepared by the supercritical fluid (SCF) particle formation method described herein and one or more fluorocarbon, hydrogen-containing fluorocarbon or hydrogen-containing chlorofluorocarbon propellants is a further aspect of the present invention.
In another aspect of the present invention, there is provided an aerosol pharmaceutical formulation comprising salmeterol xinafoate in a form with a dynamic bulk density of less than 0.1 g.cmxe2x88x923, preferably in the range between 0.01 and 0.1 g.cmxe2x88x923 and, in particular, in the range between 0.01 and 0.075 g.cmxe2x88x923 and a fluorocarbon, hydrogen-containing fluorocarbon or hydrogen-containing chlorofluorocarbon propellant.
The dynamic bulk density (W) is indicative of a substance""s fluidisability and is defined as:   W  =                              (                      P            -            A                    )                ⁢        C            100        +    A  
where P is the packed bulk density (g.cmxe2x88x923), A is the aerated bulk density (g.cmxe2x88x923) and C is the compressibility (%) where C is calculated by the equation:   C  =                    P        -        A            P        xc3x97    100  
Clearly, a low figure for W corresponds to a high degree of fluidisability.
When compared against conventionally crystallised salmeterol xinafoate, both before and after micronisation, the salmeterol xinafoate employed in the present invention exhibits a significantly lower dynamic bulk density, as illustrated in Table 2 (see Example 1 below).
It will be appreciated that in the case of an inhaled pharmaceutical, such as salmeterol xinafoate, it is particularly desirable to produce a drug substance which is readily fluidisable, thereby potentially improving its inhalation properties.
The salmeterol xinafoate used in the formulations of the present invention is observed to have improved handling and fluidising characteristics compared with conventionally crystallised salmeterol xinafoate.
Furthermore, the particle size and shape of the salmeterol xinafoate used in the formulations of the present invention can be controlled as illustrated by the electron-micrographs herein.
Preferably, the salmeterol xinafoate employed in the formulations of the present invention is within the particle size range suitable for pharmaceutical dosage forms to be delivered by inhalation or insufflation. A suitable particle size range for this use is 1 to 10 microns, preferably 1 to 5 microns. Particles generally have a uniform particle size distribution, as measured by a uniformity coefficient of from 1 to 100, typically 1 to 20 e.g. 5 to 20.
The salmeterol xinafoate employed in the formulations of the present invention typically has a low cohesivity, for example of 0 to 20%, preferably 0 to 5% employing methods of measurement based on those described by R L Carr in Chemical Engineering 1965, 163-168.
It has also been found that conventionally crystallised salmeterol xinafoate, when studied by differential scanning calorimetry (DSC), shows a transition between two forms (hereinafter xe2x80x9cPolymorph Ixe2x80x9d and xe2x80x9cPolymorph IIxe2x80x9d) occurring between 120xc2x0 C. and 140xc2x0 C. A DSC profile for conventionally crystallised salmeterol xinafoate showing the characteristic two peaks for Polymorphs I and II is shown in FIG. 3. However, use of the supercritical fluid particle formation method and apparatus of WO95/01324 allows the preparation of substantially pure Polymorph I, substantially pure Polymorph II or controlled mixtures of the two polymorphic forms. The prepared polymorphs are also stable, meaning that there is no transition from one polymorph to another observed under the DSC conditions.
Thus, the present invention also provides a pharmaceutical aerosol formulation which comprises substantially pure particulate Polymorph I salmeterol xinafoate and a fluorocarbon, hydrogen-containing fluorocarbon or hydrogen-containing chlorofluorocarbon propellant. Also provided is a pharmaceutical aerosol formulation which comprises substantially pure particulate Polymorph II salmeterol xinafoate and a fluorocarbon, hydrogen-containing fluorocarbon or hydrogen-containing chlorofluorocarbon propellant. By xe2x80x9csubstantially purexe2x80x9d polymorph is meant a composition containing a first polymorph, but essentially none of the other polymorph; by xe2x80x9cessentially nonexe2x80x9d is meant less than 0.5% w/w based upon the first polymorph, for example 0.1% or less.
The present invention also provides the use of essentially pure Polymorph I of salmeterol xinafoate in the manufacture of a medicament comprising propellant 134a for the treatment of respiratory disorders.
The salmeterol xinafoate prepared by the supercritical fluid particle formation method may be used to prepare a pharmaceutical composition which further comprises a pharmaceutically acceptable carrier. Preferred carriers include, for example polymers e.g. starch and hydroxypropylcellulose, silicon dioxide, sorbitol, mannitol and lactose e.g. lactose monohydrate. Using the supercritical fluid particle formation method and apparatus, salmeterol xinafoate and a carrier may be co-crystallised together to form multicomponent particles comprising both salmeterol xinafoate and carrier. Pharmaceutical formulations comprising such multicomponent particles and a fluorocarbon, hydrogen-containing fluorocarbon or hydrogen-containing chlorofluorocarbon propellant represent a further aspect of the invention. In a preferred aspect, the invention provides a pharmaceutical composition comprising salmeterol xinafoate and lactose in the form of multicomponent particles.
The use of supercritical fluids (SCFs) and the properties thereof has been extensively documented, see for instance, J. W. Tom and P. G. Debendetti, xe2x80x9cParticle Formation with Supercritical Fluidsxe2x80x94A Reviewxe2x80x9d, J. Aerosol. Sci., 22 (5), 555-584 (1991). Briefly, a supercritical fluid can be defined as a fluid at or above its critical pressure (Pc) and critical temperature (Tc) simultaneously. Supercritical fluids have been of considerable interest, not least because of their unique properties. These characteristics include:
High diffusivity, low viscosity and low surface tension compared with liquids.
Large compressibility of supercritical fluids compared with the ideal gas implies large changes in fluid density for slight changes in pressure, which in turn results in highly controllable solvation power. Supercritical fluid densities typically range from 0.1-0.9 g/ml under normal working conditions. Thus, selective extraction with one supercritical fluid is possible.
Many supercritical fluids are normally gases under ambient conditions, which eliminates the evaporation/concentration step needed in conventional liquid extraction.
Most of the commonly used supercritical fluids create non-oxidising or non-degrading atmospheres for sensitive and thermolabile compounds, due to their inertness and moderate temperatures used in routine working conditions. Carbon dioxide is the most extensively used SCF due to its cheapness, non-toxicity, non-flammability and low critical temperature.
These characteristics have led to the development of several techniques of extraction and particle formation utilising supercritical fluids, including that described in WO95/01324.
As used herein, the term xe2x80x9csupercritical fluidxe2x80x9d means a fluid at or above its critical pressure (Pc) and critical temperature (Tc) simultaneously. In practice, the pressure of the fluid is likely to be in the range 1.01 Pc-7.0 Pc, and its temperature in the range 1.01 Tc-4.0 Tc.
The term xe2x80x9cvehiclexe2x80x9d means a fluid which dissolves a solid or solids, to form a solution, or which forms a suspension of a solid or solids which do not dissolve or have a low solubility in the fluid. The vehicle can be composed of one or more fluids.
As used herein, the term xe2x80x9csupercritical solutionxe2x80x9d means a supercritical fluid which has extracted and dissolved the vehicle.
The term xe2x80x9cdispersionxe2x80x9d means the formation of droplets of the vehicle containing at least one substance in solution or suspension.
The term xe2x80x9cparticulate productxe2x80x9d includes products in a single-component or multi-component (e.g. intimate mixtures of one component in a matrix of another) form.
Suitable chemicals for use as supercritical fluids include carbon dioxide, nitrous oxide, sulphur hexafluoride, xenon, ethylene, chlorotrifluoromethane, ethane and trifluoromethane. Particularly preferred is carbon dioxide.
The supercritical fluid may optionally contain one or more modifiers, for example, but not limited to, methanol, ethanol, isopropanol or acetone. When used, the modifier preferably constitutes not more than 20%, and more particularly constitutes between 1 and 10%, of the supercritical fluid.
The term xe2x80x9cmodifierxe2x80x9d is well known to those persons skilled in the art. A modifier (or co-solvent) may be described as a chemical which, when added to a supercritical fluid, changes the intrinsic properties of the supercritical fluid in or around the critical point.
It will be appreciated that the precise conditions of operation of the present apparatus will be dependent upon the choice of supercritical fluid and whether or not modifiers are present. Table 1 lists the critical pressure and temperatures for some selected fluids:
In practice, it may be preferable to maintain the pressure inside the particle formation vessel substantially in excess of the Pc (for instance, 100-300 bar for carbon dioxide) whilst the temperature is slightly above the Tc (e.g. 40-60xc2x0 C. for carbon dioxide).
The flow rates of the supercritical fluid and/or the vehicle may also be controlled so as to achieve a desired particle size, shape and/or form. Typically, the ratio of the vehicle flow rate to the supercritical fluid flow rate will be between 0.001 and 0.1, preferably between 0.01 and 0.07, more preferably around 0.03.
The method described herein preferably additionally involves collecting the particulate product following its formation. It may also involve recovering the supercritical solution formed, separating the components of the solution and recycling one or more of those components for future use.
It will be appreciated that the choice of a suitable combination of supercritical fluid, modifier (where desired) and vehicle will be well within the capabilities of a person of ordinary skill in the art.
In the present case, the product to be formed is a pharmaceutical compound, salmeterol xinafoate, for which a suitable solvent may be, for example, methanol, ethanol, isopropanol, acetone or any mixture thereof.
Control of parameters such as size and shape in the particulate product will be dependent upon the operating conditions used when carrying out the supercritical fluid particle formation method. Variables include the flow rates of the supercritical fluid and/or the vehicle containing the drug, the concentration of the drug in the vehicle, and the temperature and pressure inside the particle formation vessel.
The apparatus described herein and its use provide the opportunity for manufacturing dry particulate products with controlled particle size, shape and morphology by offering such control over the working conditions, especially the pressure, utilising, for example, an automated back-pressure regulator such as model number 880-81 produced by Jasco Inc. Such control can eliminate pressure fluctuation across the particle formation vessel and ensures a more uniform dispersion by the supercritical fluid of the vehicle containing drug substance, with narrow droplet size distribution, during the particle formation process. There is little or no chance that the dispersed droplets will reunite to form larger droplets since the dispersion occurs by the action of the supercritical fluid which also ensures thorough mixing with the vehicle and rapidly removes the vehicle from the drug substance, leading to particle formation.
The means for the co-introduction of the supercritical fluid and the vehicle into the particle formation vessel preferably allows for them to be introduced with concurrent directions of flow, and more preferably takes the form of a coaxial nozzle as described below. This ensures no contact between the formed particles and the vehicle fluid around the nozzle tip area. Such contact would reduce control of the final product size and shape. Extra control over the droplet size, in addition to that provided by nozzle design, is achieved by controlling the flow rates of the supercritical fluid and the vehicle fluid. At the same time, retaining the particles in the particles formation vessel eliminates the potential of contact with the vehicle fluid that might otherwise take place on depressurising the supercritical solution. Such contact would affect the shape and size, and potentially the yield, of the product.
A further advantage of the apparatus described herein is that it can allow particle formation to occur in a completely closed environment, i.e. in a closed particle formation vessel. The apparatus can be sealed from the atmosphere, making it easy to maintain sterile operating conditions and also reducing the risk of environmental pollution and it can also be kept free of oxygen, moisture or other relevant contaminants.
The final aerosol formulation desirably contains 0.03-0.13% w/w, preferably 0.07% w/w, of medicament relative to the total weight of the formulation.
The propellants for use in the invention may be any fluorocarbon, hydrogen-containing fluorocarbon or hydrogen-containing chlorofluorocarbon propellant or mixtures thereof having a sufficient vapour pressure to render them effective as propellants. Preferably the propellant will be a non-solvent for the medicament. Suitable propellants include, for example, C1-4hydrogen-containing chlorofluorocarbons such as CH2ClF, CClF2CHClF, CF3CHClF, CHF2CClF2, CHClFCHF2, CF3CH2Cl and CClF2CH3; C1-4hydrogen-containing fluorocarbons such as CHF2CHF2, CF3CH2F, CHF2CH3 and CF3CHFCF3; and perfluorocarbons such as CF3CF3 and CF3CF2CF3.
Where mixtures of the fluorocarbon, hydrogen-containing fluorocarbon or hydrogen-containing chlorofluorocarbon propellants are employed they may be mixtures of the above identified compounds or mixtures, preferably binary mixtures, with other fluorocarbon, hydrogen-containing fluorocarbon or hydrogen-containing chlorofluorocarbon propellants for example CHClF2, CH2F2 and CF3CH3. Preferably a single fluorocarbon, hydrogen-containing fluorocarbon or hydrogen-containing chlorofluorocarbon is employed as the propellant. Particularly preferred as propellants are C1-4hydrogen-containing fluorocarbons such as 1,1,1,2-tetrafluoroethane (CF3CH2F) and 1,1,1,2,3,3,3-heptafluoro-n-propane (CF3CHFCF3), particularly 1,1,1,2-tetrafluoroethane.
It is desirable that the formulations of the invention contain no components which may provoke the degradation of stratospheric ozone. In particular it is desirable that the formulations are substantially free of chlorofluorocarbons such as CCl3F, CCl2F2 and CF3CCl3.
The propellant may additionally contain a volatile adjuvant such as a saturated hydrocarbon for example propane, n-butane, isobutane, pentane and isopentane or a dialkyl ether for example dimethyl ether. In general, up to 50% w/w of the propellant may comprise a volatile hydrocarbon, for example 1 to 30% w/w. However, formulations which are substantially free of volatile adjuvants are preferred.
The benefits of the present invention may be achieved without the use of any surfactant or cosolvent in the composition, or with relatively low levels of such components, and without the necessity to pre-treat the medicament prior to dispersal in the propellant. However, it is further envisaged that certain formulations of the present invention may include liquid components of higher polarity than the propellant employed. Polarity may be determined for example, by the method described in European Patent Application Publication No. 0327777. In particular, where such components are included, alcohols such as ethanol are preferable. However, higher polarity liquid components are preferably included at relatively low concentrations, for example less than 5%, preferably less than 1% w/w based upon the fluorocarbon or hydrogen-containing chlorofluorocarbon. Particular preferred formulations may contain essentially no higher polarity liquid components, by xe2x80x9cessentially noxe2x80x9d is meant less than 0.1% w/w based upon propellant, for example 0.0001% or less.
Where a surfactant is employed, it is selected from those which are physiologically acceptable upon administration by inhalation such as oleic acid, sorbitan trioleate (Span R 85), sorbitan mono-oleate, sorbitan monolaurate, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monooleate, natural lecithin, fluorinated and perfluorinated surfactants including fluorinated lecithins, fluorinated phosphatidylcholines, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, block copolymers of oxyethylene and oxypropylene, synthetic lecithin, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glyceryl monooleate, glyceryl monostearate, glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol, polyethylene glycol 400, cetyl pyridinium chloride, benzalkonium chloride, olive oil, glyceryl monolaurate, corn oil, cotton seed oil and sunflower seed oil.
If it is desired to provide a formulation in which the particulate medicament is pre-coated with surfactant, the use of substantially non-ionic surfactants which have reasonable solubility in substantially non-polar solvents is frequently advantageous since it facilitates coating of the medicament particles using solutions of surfactant in non-polar solvents in which the medicament has limited or minimal solubility. The particulate drug, with its dry coating of surfactant may than be suspended in propellant, optionally with a co-solvent such as ethanol. Such formulations are described in WO92/08446 and WO92/08447.
A particularly preferred embodiment of the invention provides a pharmaceutical aerosol formulation consisting essentially of salmeterol xinafoate, as prepared by the supercritical fluid particle formation process described herein, and a fluorocarbon, hydrogen-containing fluorocarbon or hydrogen-containing chlorofluorocarbon propellant.
It will be appreciated by those skilled in the art that the aerosol formulations according to the invention may, if desired, contain a combination of two or more active ingredients. Aerosol compositions containing two active ingredients (in a conventional propellant system) are known, for example, for the treatment of respiratory disorders such as asthma. Accordingly, the present invention further provides aerosol formulations in accordance with the invention which contain salmeterol xinafoate and one or more additional particulate medicaments. Medicaments may be selected from any other suitable drug useful in inhalation therapy and which may be presented in a form which is substantially completely insoluble in the selected propellant. Appropriate medicaments may thus be selected from, for example, salbutamol, fluticasone propionate or beclomethasone dipropionate; analgesics, e.g. codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g. diltiazem; antiallergics, e.g. cromoglycate, ketotifen or nedocromil; antiinfectives e.g. cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine; antihistamines, e.g. methapyrilene; anti-inflammatories, e.g. flunisolide, budesonide, tipredane or triamcinolone acetonide; antitussives, e.g. noscapine; bronchodilators, e.g. ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, terbutaline, isoetharine, tulobuterol, (xe2x88x92)-4-amino-3,5-dichloro-xcex1-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzenemethanol or orciprenaline; diuretics, e.g. amiloride; anticholinergics e.g. ipratropium, atropine or oxitropium; hormones, e.g. cortisone, hydrocortisone or prednisolone; xanthines e.g. aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; and therapeutic proteins and peptides, e.g. insulin or glucagon. It will be clear to a person skilled in the art that, where appropriate, the medicaments may be used in the form of salts (e.g. as alkali metal or amine salts or as acid addition salts) or as esters (e.g. lower alkyl esters) or as solvates (e.g. hydrates) to optimise the activity and/or stability of the medicament and/or to minimise the solubility of the medicament in the propellant.
Particularly preferred aerosol drug combination formulations contain salmeterol as the xinafoate salt in combination with an antiinflammatory steroid such as a beclomethasone ester (e.g. the dipropionate) or a fluticasone ester (e.g. the propionate) or an antiallergic such as cromoglycate (e.g. the sodium salt). Combinations of salmeterol and fluticasone propionate or beclomethasone dipropionate are preferred, especially salmeterol xinafoate and fluticasone propionate. In particularly preferred combined formulations, each particulate drug will be of controlled particle size, shape and morphology such as may be formed by means of supercritical fluid particle formation as described herein.
The formulations of the present invention may be prepared by dispersal of the particulate salmeterol xinafoate (and carrier or additional drug if present) in the selected propellant in an appropriate container, e.g. with the aid of sonication. The process is desirably carried out under anhydrous conditions to obviate any adverse effects of moisture on suspension stability.
The chemical and physical stability and the pharmaceutical acceptability of the aerosol formulations according to the invention may be determined by techniques well known to those skilled in the art. Thus, for example, the chemical stability of the components may be determined by HPLC assay, for example, after prolonged storage of the product. Physical stability data may be gained from other conventional analytical techniques such as, for example, by leak testing, by valve delivery assay (average shot weights per actuation), by dose reproducibility assay (active ingredient per actuation) and spray distribution analysis.
The particle size distribution of the aerosol formulations according to the invention may be measured by conventional techniques, for example by cascade impaction or by the xe2x80x9cTwin Impingerxe2x80x9d analytical process. As used herein reference to the xe2x80x9cTwin Impingerxe2x80x9d assay means xe2x80x9cDetermination of the deposition of the emitted dose in pressurised inhalations using apparatus Axe2x80x9d as defined in British Pharmacopoeia 1988, pages A204-207, Appendix XVII C. Such techniques enable the xe2x80x9crespirable fractionxe2x80x9d of the aerosol formulations to be calculated. As used herein reference to xe2x80x9crespirable fractionxe2x80x9d means the amount of active ingredient collected in the lower impingement chamber per actuation expressed as a percentage of the total amount of active ingredient delivered per actuation using the twin impinger method described above. The formulations according to the invention, containing salmeterol xinafoate of mean particle size between 1 and 10 microns, preferably have a respirable fraction of 30% or more by weight of the medicament, desirably 30 to 70%, for example 30 to 50%.
The formulations according to the invention may be filled into canisters suitable for delivering pharmaceutical aerosol formulations. Canisters generally comprise a container capable of withstanding the vapour pressure of the propellant used such as a plastic or plastic-coated glass bottle or preferably a metal can, for example an aluminium can which may optionally be anodised, lacquer-coated and/or plastic-coated, which container is closed with a metering valve. Canisters lined with a fluorocarbon polymer (especially polytetrafluoroethylene (PTFE)) in combination with a non-fluorocarbon polymer (especially polyethersulphone (PES) are preferred. The metering valves are designed to deliver a metered amount of the formulation per actuation and incorporate a gasket to prevent leakage of propellant through the valve. The gasket may comprise any suitable elastomeric material such as for example low density polyethylene, chlorobutyl, black and white butadiene-acrylonitrile rubbers, butyl rubber and neoprene. Suitable valves are commercially available from manufacturers well known in the aerosol industry, for example, from Valois, France (e.g. DF10, DF30, DF60), Bespak plc, UK (e.g. BK300, BK356, BK357) and 3M-Neotechnic Ltd, UK (e.g. Spraymiser(trademark)).
Conventional bulk manufacturing methods and machinery well known to those skilled in the art of pharmaceutical aerosol manufacture may be employed for the preparation of large scale batches for the commercial production of filled canisters. Thus, for example, in one bulk manufacturing method a metering valve is crimped onto an aluminium can to form an empty canister. The particulate medicament is added to a charge vessel and liquified propellant is pressure filled through the charge vessel into a manufacturing vessel. The drug suspension is mixed before recirculation to a filling machine and an aliquot of the drug suspension is then filled through the metering valve into the canister. Typically, in batches prepared for pharmaceutical use, each filled canister is check-weighed, coded with a batch number and packed into a tray for storage before release testing.
Each filled canister is conveniently fitted into a suitable channelling device prior to use to form a metered dose inhaler for administration of the medicament into the lungs or nasal cavity of a patient. Suitable channelling devices comprise for example a valve actuator and a cylindrical or cone-like passage through which medicament may be delivered from the filled canister via the metering valve to the nose or mouth of a patient e.g. a mouthpiece actuator. Metered dose inhalers are designed to deliver a fixed unit dosage of medicament per actuation or xe2x80x9cpuffxe2x80x9d, for example in the range of 10 to 500 micrograms medicament per puff.
Administration of medicament may be indicated for the treatment of mild, moderate or severe acute or chronic symptoms or for prophylactic treatment. It will be appreciated that the precise dose administered will depend on the age and condition of the patient, the particular particulate medicament(s) used and the frequency of administration and will ultimately be at the discretion of the attendant physician. When combinations of medicaments are employed the dose of each component of the combination will in general be that employed for each component when used alone. Typically, administration may be one or more times, for example from 1 to 8 times per day, giving for example 1,2,3 or 4 puffs each time.
Suitable daily doses may be, for example, in the range 50 to 200 microgram of salmeterol, depending on the severity of the disease and, for example, each valve actuation may deliver 25 microgram salmeterol. Typically each filled canister for use in a metered dose inhaler contains 60, 120, 200 or 240 metered doses or puffs of medicament.
The filled canisters and metered dose inhalers described herein comprise further aspects of the present invention.
A still further aspect of the present invention comprises a method of treating respiratory disorders such as, for example, asthma or chronic obstructive pulmonary disease (COPD), which comprises administration by inhalation of an effective amount of a formulation as herein described.